结节性淋巴细胞优先型霍奇金淋巴瘤中的肿瘤内及外周血TIGIT与PD-1作为免疫生物标志物

Intra-tumoral and peripheral blood TIGIT and PD-1 as immune biomarkers in nodular lymphocyte predominant Hodgkin lymphoma

AMERICAN JOURNAL OF HEMATOLOGY

影响因子:9.9

分区:医学1区 Top / 血液学2区

发表日期:2024 Nov

作者: Jay Gunawardana, Soi C Law, Muhammed B Sabdia, Éanna Fennell, Aoife Hennessy, Ciara I Leahy, Paul G Murray, Karolina Bednarska, Sandra Brosda, Judith Trotman, Leanne Berkahn, Andreea Zaharia, Simone Birch, Melinda Burgess, Dipti Talaulikar, Justina N Lee, Emily Jude, Eliza A Hawkes, Sanjiv Jain, Karthik Nath, Cameron Snell, Fiona Swain, Joshua W D Tobin, Colm Keane, Mohamed Shanavas, Emily Blyth, Christian Steidl, Kerry Savage, Pedro Farinha, Merrill Boyle, Barbara Meissner, Michael R Green, Francisco Vega, Maher K Gandhi

DOI: 10.1002/ajh.27459

摘要

在经典霍奇金淋巴瘤（cHL）中，免疫检查点阻断（ICB）的反应性与特定的肿瘤微环境（TME）和外周血特征有关。关于结节性淋巴细胞优先型霍奇金淋巴瘤（NLPHL）中ICB的作用尚未明确。为探讨其潜力，我们采用多组学整合分析比较了NLPHL与cHL的TME和外周血特征。在121例NLPHL和114例cHL患者的研究中发现，NLPHL中程序性细胞死亡蛋白1（PD-1）和T细胞免疫球蛋白与ITIM结构域（TIGIT）基因表达水平比cHL高出2倍以上。多重免疫组化显示，NLPHL中肿瘤内PD-1+（和/或TIGIT+）CD4+ T细胞和PD-1+CD8+ T细胞的蛋白表达明显升高，且包括与淋巴细胞优先型（LP）和霍奇金Reed-Sternberg（HRS）细胞形成包围的T细胞。在NLPHL中，肿瘤内PD-1+CD4+ T细胞常表达T细胞因子转录因子-1（TCF-1），这是对ICB增强T细胞反应的标志。NLPHL与cHL的外周血特征也不同，表现为NLPHL中TH1、TH2及调节性CD4+ T细胞中PD-1+TIGIT+的水平较高，而循环中的PD-1+CD4+ T细胞TCF-1水平也较高。有趣的是，无论是哪种淋巴瘤，血液中高度扩增的克隆性TIGIT+PD-1+CD4+和TIGIT+PD-1+CD8+ T细胞也存在于肿瘤微环境中，表明表达免疫检查点的T细胞在肿瘤内外循环。体外实验显示，ICB能够减少包围LP和HRS细胞的包围圈，提示破坏包围圈可能是ICB在HL中的作用机制。总体而言，结果表明进一步评估ICB在NLPHL中的应用具有潜在价值。

Abstract

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.